Human growth hormone, which is produced in the human pituitary gland, is a single-chain polypeptide of 191 amino acids having a molecular weight of about 22,000 daltons. Human growth hormone is used mainly for treating pituitary dwarfism in children (Endocrinol. Rev. 4, 155, 1983).
Human growth hormone tends to be unstable in pharmaceutical preparations. The degradation products of growth hormone, including deamidated or sulfoxylated products and dimer or polymer forms, can be generated in solution. A predominant chemical degradation reaction of human growth hormone is deamidation, which especially takes place at the asparagine residue at position 149, by direct hydrolysis or via a cyclic succinimide intermediate to form L-asp-hGH, L-iso-asp-hGH, D-asp-hGH and D-iso-asp-hGH. At present, these deamidated products of human growth hormone are not believed to have toxic or altered biological activity or receptor binding properties, but the conformational stability of the sulfoxides is reduced compared to native human growth hormone.
The deamidated human growth hormone is undesirable for use as a medicament because it undergoes quality deterioration, despite having unaltered biological activity, and its allowable content is thus usually provided by the public specification for purity. Also, the formation of aggregates of growth hormone, such as dimers or polymers, causes undesired immunogenicity, leading to a safety problem in vivo, and suspended solids, leading to an appearance problem, thereby causing patients displeasure.
Protein stability is closely related with water. Human growth hormone is mostly commercially available in a lyophilized formulation to increase its stability that must be reconstituted prior to use. However, many studies have been conducted on liquid formulations of human growth hormone in order to improve the convenience of medical doctors and patients. For example, U.S. Pat. No. 6,448,225, relating to Genentech's Nutropin AQ, discloses an aqueous formulation of human growth hormone, comprising human growth hormone, mannitol, a buffer and a non-ionic surfactant, wherein citrate buffer was exemplified as being preferable. Korean Pat. Application No. 10-1999-0001217 provides a stable aqueous formulation, in which human growth hormone is dissolved in a buffer solution, which is prepared using a slightly to moderately acidic buffer, preferably a maleate buffer, containing benzalkonium chloride. Korean Pat. Application No. 10-1998-0052483 describes a pharmaceutically-stable liquid formulation of human growth hormone, wherein a buffer solution consisting of sodium acetate and sodium glutamate is preferred. Also, in Korean Pat. Application No. 10-1994-0702139, Novo Nordisk A/S describes a pharmaceutical formulation comprising a growth hormone, and an amino acid selected from the group consisting of Asp, Ile, Val, Leu and His, or a derivative of histidine, or a peptide comprising at least one basic amino acid and at least one acidic amino acid, and a non-ionic detergent, such as polysorbate or poloxamer. Novo Nordisk A/S currently markets Norditropin SimpleXx, which contains human growth hormone, histidine buffer, a non-ionic surfactant, sodium chloride, and a preservative.
However, although a variety of attempts have been made to provide an liquid formulation of growth hormone, as described above, there is a need for a stabler liquid formulation of growth hormone.